A comprehensive understanding of the fundamental mechanisms driving ethanol toxicity augments the development of highly effective, targeted therapies to both prevent and treat health problems caused by excessive alcohol consumption. The long term goal of this study aims to elucidate the protective functions of aldehyde dehydrogenase 7A1 (ALDH7A1) during ethanol-induced oxidative stress. Ethanol metabolism elevates reactive oxygen species triggering lipid peroxidation (LPO) throughout tissues. The oxidation of polyunsaturated fatty acids in cell membranes via LPO generates over two hundred different types of reactive aldehydes. These molecules bind to protein, DNA and other compounds within cells causing enzyme inactivation, DNA damage and impaired cellular homeostasis. Ethanol-induced oxidative stress also impairs methionine metabolism thereby promoting tissue damage through the depletion of S-adenosylmethionine (SAM). SAM is the principle biological methyl donor and required for protein, phospholipid and DNA methylation. In the liver, chronic ethanol consumption both dramatically elevates LPO-derived aldehyde production and significantly depletes SAM pools. The combined effect of these processes damage cells and contribute to alcohol-induced liver damage. Our preliminary data suggests that ALDH7A1 may be a key player in protecting against ethanol-mediated tissue damage. We have shown that ALDH7A1 metabolizes a number of toxic LPO-derived aldehydes. Furthermore, our data indicates ALDH7A1 generates betaine from betaine aldehyde. Betaine is an important osmolyte and methyl-group donor. Supplementation of betaine during chronic ethanol exposure has been shown to decrease oxidative stress and prevent ethanol-induced liver damage by serving as a precursor for SAM biosynthesis. Our working hypothesis is that ALDH7A1 is involved in cellular defense against ethanol induced-hepatotoxicity by metabolizing LPO-derived aldehydes as well as maintaining methionine homeostasis by generating betaine. We will 1) test the hypothesis that ALDH7A1 protects against ethanol-induced oxidative stress in vitro. By manipulating the levels of ALDH7A1 expression in cell culture, we can gain a better understanding of the role it plays during ethanol metabolism. We will also 2) test the hypothesis that ALDH7A1 protects against ethanol-induced oxidative stress using a liver-specific Aldh7a1 knockout mouse. Liver histology, function and damage during chronic ethanol treatment will be studied in mice lacking ALDH7A1 as compared to control animals. The contribution of ALDH7A1 during ethanol metabolism has yet to be determined and the proposed studies intend to expand upon the above mentioned relationships. Results from this study will broaden our understanding of the processes underlying ethanol-induced tissue damage and support the development of effective therapeutic options for patients suffering from alcohol-related diseases. PUBLIC HEALTH RELEVANCE: Aldehyde dehydrogenase 7A1 (ALDH7A1) is enzyme that removes many toxic molecules produced during ethanol metabolism. Recently it was discovered the enzyme also generates betaine which is compound known to prevent ethanol-related pathologies. This long term goal of this project is to elucidate the protective functions of ALDH7A1 during excessive alcohol consumption.